School of Chinese Materia Medica, Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
School of Chinese Materia Medica, Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
Phytomedicine. 2024 Nov;134:155973. doi: 10.1016/j.phymed.2024.155973. Epub 2024 Aug 26.
Inflammatory bowel disease (IBD) is a chronic and relapsing disease marked by chronic tissue inflammation that alters the integrity and function of the gut, seriously impacting patient health and quality of life. Aucklandiae Radix (AR), known as Mu Xiang in Chinese, is a traditional Chinese medicine documented in Chinese Pharmacopoeia with effects of strengthening the intestine and stopping diarrhea. However, the potential of AR in treating intestinal inflammation and its underlying mechanism have yet to be further elucidated.
The objective of this study was to explore the protective effect and the potential mechanism attributable to AR for treating ulcerative colitis (UC).
A murine model of UC was constructed using dextran sulfate sodium (DSS) to examine the therapeutic potential of AR in alleviating inflammation and modulating the immune response. Advanced techniques such as photocrosslinking target fishing technique, click chemistry, Western blot analysis, real-time quantitative PCR, flow cytometry, immunofluorescence, and immunohistochemistry were employed to unveil the therapeutic mechanism of AR for treating IBD.
AR decreased disease activity index (DAI) score to alleviate the course of IBD through ameliorating intestinal barrier function in DSS-induced mice. Furthermore, AR suppressed NF-κB and NLRP3 pathways to reduce the release of pro-inflammatory factors interleukin-6 and 1β (IL-6 and IL-1β) and tumor necrosis factor α (TNF-α), allowing to alleviate the inflammatory response. Flow cytometry revealed that AR could reduce the accumulation of intestinal macrophages and neutrophils, maintaining intestinal immune balance by regulating the ratio of Treg to Th17 cells. It was worth noting that pyruvate kinase isozyme type M2 (PKM2) served as a potential target of AR using the photocrosslinking target fishing technology, which was further supported by cellular thermal shift assay (CETSA), drug affinity target stability (DARTS), and PKM2 knockdown experiments.
AR targeted PKM2 to inhibit NF-κB and NLRP3 pathways, thereby modulating the inflammatory response and immunity to alleviate DSS-induced UC. These findings suggested the potential of AR in the treatment of UC and AR as a candidate for developing PKM2 regulators.
炎症性肠病（IBD）是一种慢性复发性疾病，其特征为慢性组织炎症，改变肠道的完整性和功能，严重影响患者的健康和生活质量。中药木香（AR），又名木香，收载于《中国药典》，具有健脾止泻的功效。然而，AR 治疗肠道炎症的潜力及其潜在机制尚待进一步阐明。
本研究旨在探讨 AR 治疗溃疡性结肠炎（UC）的保护作用及其潜在机制。
采用葡聚糖硫酸钠（DSS）构建 UC 小鼠模型，考察 AR 缓解炎症和调节免疫反应的治疗潜力。运用光交联靶向捕获技术、点击化学、Western blot 分析、实时定量 PCR、流式细胞术、免疫荧光和免疫组织化学等先进技术，揭示 AR 治疗 IBD 的治疗机制。
AR 通过改善 DSS 诱导的小鼠肠道屏障功能，降低疾病活动指数（DAI）评分，缓解 IBD 病程。此外，AR 抑制 NF-κB 和 NLRP3 通路，减少促炎因子白细胞介素-6 和 1β（IL-6 和 IL-1β）和肿瘤坏死因子-α（TNF-α）的释放，从而缓解炎症反应。流式细胞术显示，AR 可减少肠道巨噬细胞和中性粒细胞的积累，通过调节 Treg/Th17 细胞的比例维持肠道免疫平衡。值得注意的是，利用光交联靶向捕获技术发现丙酮酸激酶同工酶 M2（PKM2）是 AR 的潜在靶点，细胞热转移分析（CETSA）、药物亲和靶标稳定性（DARTS）和 PKM2 敲低实验进一步证实了这一点。
AR 通过靶向 PKM2 抑制 NF-κB 和 NLRP3 通路，调节炎症反应和免疫，缓解 DSS 诱导的 UC。这些发现表明 AR 在治疗 UC 方面具有潜力，AR 可作为开发 PKM2 调节剂的候选药物。
